Evaluation of [18F]RM273 for sigma2-receptor imaging in an experimental orthotopic glioblastoma model

Objectives
The proven suitability of the sigma2 receptor as marker for the proliferative status of solid tumors of the body [1] has promoted efforts to develop brain-targeted radioligands for sigma2 receptor imaging in neuro-oncological diseases as well. Accordingly, based on the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds we designed a series of novel fluorinated derivatives for 18F-labelling and investigated the most promising sigma2 receptor ligand in a rat model for glioma.
Methods
[18F]RM273 (2-[4-(6-[18F]fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) has been obtained by automated synthesis by Cu-mediated oxidative radiofluorination of the aryl boronic acid pinacol ester precursor. Wildtype mice (female, CD1; n = 4) and rats with intracranial implanted orthotopic F98 glioma (male, F344; n = 2) were injected with the radiotracer (mice: 7.2±1.1 MBq; rats: 21–25 MBq) and investigated by dynamic PET (nanoScan®PET-1T MRI). Complementary ex vivo metabolite as well as in vitro autoradiographic studies were performed in mice after intravenous injection and in rat with cryosections of the brain of one F98 bearing animal, respectively [2].
Results
[18F]RM273 has been produced with a molar activity of 69–233 GBq/μmol at moderate radiochemical yield (8%) and high purity (≥99%). A mean standardized uptake value (SUV) of 1.3 at 2.25 min p.i. in the brain of wildtype CD1 mice indicates fast and adequate penetration of the blood-brain barrier. The polar radiometabolites of [18F]RM273 discovered in blood plasma of mice were not detectable in the brain extracts (100 % parent fraction at 30 min p.i.). The binding pattern of [18F]RM273 in vitro in cryosections of the glioma brain indicates target-specific binding towards the F98 glioma (complete displacement by co-incubation with 1 µM ISO-I) with an about 3-fold higher density of binding sites in comparison to the healthy brain [2]. Also by PET the F98 glioma could be delineated clearly with mean SUVs at 30–60 min p.i. of 0.8–1.3 in the tumor and 0.5 in the contralateral region.
Conclusions
The reasonable brain penetration in rodents as well as the tumor specific accumulation of [18F]RM273 in the F98 glioma indicates the suitability of this radioligand for future imaging studies regarding the role of sigma2 receptors in neuro-oncological diseases. Our preliminary finding of a high density of sigma2 receptors in highly proliferative brain tumor cells deserves further investigation by larger sample sizes and complementation with immunohistochemistry.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (DFG: BR 1360/13-1).
References
[1] Shoghi et al. Plos One 2013, 8: e74188
[2] Moldovan et al. Int. J. Mol. Sci. 2021, 22: 5447